Advances in the Treatment of Colorectal Cancer

University of Colorado

Gastrointestinal Malignancies Program

November 2, 2013

Objectives

• What is the current state of treatment for colorectal cancer?

• What are some of the limitations of the current treatments for colorectal cancer?

• The next generation of treatments for colorectal cancer

*Source: American Cancer Society

Advances in screening

Images from ACS

Advances in colorectal cancer

http://www.cancerresearchuk.org/cancer-

info/cancerstats/types/bowel/survival/bowel-cancer-survival-statistics

5-year-survival rates

(all stages)

Colorectal Cancer in 1997 versus Today

Treatment: 5-fluorouracil

• Response rate = 10-15%

• Overall survival = 8-12 months

Treatment: 5-fluorouracil

Oxaliplatin

Irinotecan

Bevacizumab/Ziv-aflibercept

Cetuximab/Panitumumab

Regorafenib

• Response rate = 55-60%

• Overall survival has more than doubled!

Van Cutsem. N Engl J Med. 2009;360:1408; Bokemeyer C, et al. J Clin Oncol.

2009;27(5):663-671;

Falcone J, et al. J Clin Oncol. 2007;25(13):1670-1676. *Referred to from this point as aflibercept.

Chemotherapy for Colorectal Cancer

• Marked Improvements in the Last Decade

– 8 new drugs approved since 1998 (ziv-aflibercept approved

08/2012, regorafenib approved 09/2012)

– Overall survival has doubled compared to 5-fluorouracil alone

– Response rates in large trials have surpassed 60%

–

• But . . . Many Negative Studies Since 2008

– Combining EGFR/VEGFR inhibition failed

– Adjuvant cetuximab, bevacizumab failed

Advances in Understanding the Genetic Landscape of Colorectal Cancer

• On average, there are 90 genes mutated per cancer

• However, < 20 pathways will actually drive cancer development

• Most mutations are harmless

Wood et al. Science 2007.

• Some patients with stage IV disease are cured using

multi-disciplinary approaches (surgery, chemo, etc)

• Combination therapy is generally well-tolerated

• Biologics have added incremental (but sometimes

limited) benefit

• Era of personalized therapy began with KRAS

General Themes in Treating Colorectal Cancer

Treatment for metastatic colorectal cancer has improved, but . . .

Courtesy of Wells Messersmith, MD

Colorectal cancer is expensive!

5-FU (500 mg/m2) $6

Leucovorin (500 mg/m2) $85

Capecitabine (2000 mg/m2/day) $3,250

Irinotecan (180 mg/m2) / generic $2,300 / $480

Oxaliplatin (85 mg/m2) / generic $4,190 / $590

Bevacizumab (5 mg/kg) $2,560

Cetuximab (250 mg/m2) $5,120

Panitumumab (6 mg/kg) $4,360

Aflibercept (4 mg/kg) $5,380

Regorafenib (160 mg, 3/1) $5,650

1997: 6 months of 5-FU/LV costs ~$500

2012: 24 months therapy with combinations costs >$300,000

Courtesy of Lisa Thompson, PharmD

Current Cancer Treatment Strategy: One-size-fits-all

We want to find the right drugs for the right patient!

BRAF inhibition in Melanoma

BRAF Inhibition in Melanoma

Wagle et al. J Clin Oncol. 2011.

Unfortunately, colorectal cancer is complex

Our Strategy here at CU

• Develop better therapies for colon cancer

• Find ways to select the right patient for these treatments

•

• Convert the disease into a chronic medical illness rather than a terminal disease until we prevent/cure colon cancer

Roadmap of Precision Oncology

• Colorado Molecular Correlates Laboratory

– KRAS

– BRAF

– MSI

• Hereditary Cancers Clinic

– Familial Risk

Roadmap of Precision Oncology

Precision Oncology Trial @ University of Colorado

(COMIRB 12-1025: Feasibility Study of Genomic Sequencing to Find

Potential Target for Personalized Medicine in Patients with Advanced

Malignancies, PI: Elaine Lam)

KRAS Mutant Colorectal Cancer

The KRAS Pathway

RAS

ERK

RAF

MEK

Tumor Growth and Spread

EGFR

The KRAS Pathway

RAS

ERK

RAF

MEK

Tumor Growth and Spread

EGFR X

The KRAS Pathway

Mutated

KRAS

ERK

RAF

MEK

Tumor Growth and Spread

EGFR X

Ongoing Trials in KRAS Mutant CRC

• Regorafenib+FOLFIRI – c-kit, VEGFR2, BRAF

• BIBW2992 (afatinib) – EGFR, Her2 inhibitor

• Sorafenib + Irinotecan – RAF, kit, FLT-3, VEGFR-

2,3, PDGFR

• AZD6244 + Irinotecan – MEK inhibitor

• MSC1936369B + FOLFIRI – MEK inhibitor

• AZD6244 + MK 2206 – MEK inhibitor + Akt inhibitor

• PF-04691502 + PF-05212384 – PI3K + mTOR

Bench to Bedside Research in KRAS Mutant CRC

Spreafico et al. Clin Can Res 2013.

From the bench to the bedside

• Clinical trial of selumetinib in combination with cyclosporine A in patients with metastatic KRAS mutant colorectal cancer approved by the National Cancer Institute Cancer Therapy Evaluation Program

• Trial has been approved (even with the recent government shutdown)!

Help us fight colorectal cancer!

• Treatment for colorectal cancer is changing dramatically

• Research being performed will change the way we think about and treat colorectal cancer

• Clinical Trials are critical to do things better than we have in the past

Childhood ALL: Improvements in Survival

0

20

40

60

80

100

0 2 4 6 8 10 12

1996-2000(n=3421)

1989-1995(n=5121)

1983-1988(n=3711)

1978-1983(n=2984)

1975-1977(n=1313)

1972-1975(n=936)

1970-1972(n=499)

1968-1970(n=402)

%

S

u

r

v

i

v

a

l

Years from Study Entry Slide courtesy of Lia Gore, MD

Questions